African Americans (AAs) in the US are greatly over-represented not only among persons affected by HIV/AIDS and cocaine addiction, but also among persons affected by coronary artery disease (CAD) associated with HIV infection, antiretroviral therapy (ART), and cocaine use. According to our preliminary study, the rate of presence of coronary plaques/stenosis was disturbingly high in HIV-infected cardiovascularly asymptomatic AAs (27%). The rate was even higher in those who were long-term ART users or long-term cocaine users. Thus, it is critical to estimate the prevalence and incidence of coronary plaques and coronary luminal obstruction caused by both calcified and noncalcified plaques in that participating population and to examine the risk factors for coronary plaques and coronary luminal obstruction in HIV-infected cardiovascularly asymptomatic AAs. Also, since there is only a limited understanding of the mechanisms involved in the development of premature CAD in HIV-infected persons, a mechanistic study in vivo is proposed with the use of endothelial dysfunction markers and the most advanced imaging technologies to quantify coronary endothelial dysfunction - the earliest stage of atherosclerosis. The proposed specific aims are (1) To estimate the prevalence and incidence of metabolic and anthropometric abnormalities, coronary plaques, significant coronary stenoses, and left ventricular (LV) dysfunction;(2) To examine the effects of the severity of HIV infection, as measured by HIV viral load and CD4 nadir, on the presence and development of significant coronary stenoses, coronary plaques, plaque composition, and LV dysfunction;(3) To examine the effects of long-term ART (all classes), especially PI-based ART, on the presence and development of significant coronary stenoses, coronary plaques, plaque composition, and LV dysfunction;(4) To examine how cocaine use modifies the effects of the various classes of ART on the presence and development of significant coronary stenoses, coronary plaques, plaque composition, and LV dysfunction;(5) To longitudinally examine the risk factors for cardiovascular events in HIV-infected AAs with coronary plaques and significant coronary stenoses;(6) To investigate the direct effects and mechanisms of HIV infection, ART use, and cocaine use on endothelial dysfunction, as measured by endothelium-derived markers;and (7) To assess the direct effects and mechanisms of HIV infection, ART use, and cocaine use on coronary endothelial dysfunction, as measured with the use of N-13-ammonia PET/CT imaging. This study could provide critical information for understanding the mechanisms of premature CAD and lead to a breakthrough in research on prevention/intervention of CAD in HIV-infected persons and to translation of scientific discoveries into clinical applications. PUBLIC HEALTH RELEVANCE: This study will investigate why HIV-infected African Americans have high rates of heart disease. The study could provide critical information for understanding the mechanisms of premature heart disease and lead to a breakthrough in research on prevention/intervention of heart disease in HIV-infected persons and to translation of scientific discoveries into clinical applications.